Biology subjects

Lone, B.

Publications and source records attributed to Lone, B..

3 recordsLinked to original sources

bioRxiv2026

APOBEC3G expression marks a TMB-high, T cell-inflamed tumor state and is associated with response to immune checkpoint blockade in multiple cancer cohorts

Immune checkpoint therapies have transformed clinical practice; however, reliable biomarkers to predict response remain limited. Tumor mutational burden (TMB) has emerged as an important biomarker because it is thought to reflect neoantigen load, yet its predictive utility has been inconsistent. This limitation may partly arise because TMB primarily captures tumor-intrinsic immunogenicity, which is heterogeneous and does not fully reflect the state of antitumor immunity. To identify transcriptomic surrogates that capture both high mutational burden and antitumor immune activation, we investigated whether mRNA expression of mutagenic APOBEC3 family members could serve as surrogates for high TMB and T cell-rich tumors. Using a pan-cancer computational framework, we evaluated the association of four APOBEC3 genes with mutational burden, neoantigen load, immune infiltration, and immune checkpoint blockade response. Among APOBEC3A, APOBEC3B, APOBEC3G, and APOBEC3H, APOBEC3G emerged as the strongest and most consistent marker of a TMBhighCD8high and NeoantigenhighCD8high tumor phenotypes. Single-cell analyses further demonstrated that APOBEC3G is enriched in both malignant cells and T cells compared with other APOBEC3 family members, with APOBEC3G-positive CD8+ T cells exhibiting elevated activation markers including GZMB and IFNG. Importantly, retrospective analyses of 50 immune checkpoint blockade cohorts showed that APOBEC3G had the most consistent association among APOBEC3 family members with treatment response and clinical outcomes. Together, these findings identify APOBEC3G as a candidate transcriptomic marker of a TMB-associated, T cell-inflamed tumor state linked to immune-checkpoint blockade benefit, warranting further prospective validation.

genomics↗

bioRxiv2026

APOBEC3 activity and polymerase-ε deficiency are associated with distinct IDH1 R132 hotspot mutations

IDH1 R132 mutations are among the most frequent hotspot mutations in cancer, but their mutational origins have remained unclear. Here, we provide evidence that IDH1 R132C, the predominant IDH1 mutation in cholangiocarcinoma, acute myeloid leukemia, and melanoma, likely arises through APOBEC3-mediated mutagenesis. IDH1 R132C is a TpC>TpT substitution on the lagging-strand DNA template within a hairpin-forming sequence context, consistent with APOBEC3 susceptibility. In vitro assays showed that APOBEC3A can deaminate the relevant cytosine, and APOBEC3A and APOBEC3B were relatively highly expressed in tumor types with recurrent IDH1 R132C mutations. IDH1 R132G, a TpC>TpG substitution at the same site, may similarly result from APOBEC3 activity. By contrast, IDH1 R132H, the predominant IDH1 mutation in lower grade glioma and glioblastoma, is a CpG>TpG substitution at a methylated cytosine on the leading-strand DNA template, a pattern more consistent with DNA polymerase epsilon replication error. Concordantly, tumor types enriched for IDH1 R132H showed relatively low POLE expression. Together, these in vitro and bioinformatic analyses provide insight into the distinct mutational mechanisms that likely underlie recurrent IDH1 hotspot mutations in cancer.

cancer biology↗

bioRxiv2026

APOBEC3-driven neoantigen-rich cancers co-opt 1q23.3 amplification for tumor-intrinsic immune cloaking

Hypermutational processes, including those driven by the APOBEC3 family of cytidine deaminases, generate abundant neoantigens yet give rise to tumors that evade immune recognition. Here, using multi-omics analyses followed by functional validation, we identified a tumor-intrinsic immune-cloaking mechanism in neoantigen-rich epithelial cancers, characterized by coordinated suppression of antigen presentation, immune-recruiting cytokines and immune-checkpoint programs. In bladder cancer, genome-wide copy-number analysis identified recurrent 1q23.3 amplification as a genomic feature of a neoantigen-high/CD8-low tumor state. Within this locus, NECTIN4 emerged as the dominant candidate effector, outperforming extrachromosomal DNA status as a predictor of immune-neoantigen discordance. Similar associations were observed across breast and lung cancers. Functional studies demonstrated that NECTIN4 was sufficient to establish a T-cell-poor tumor microenvironment and confer resistance to PD-1 blockade in immunocompetent mice. Mechanistically, NECTIN4 engaged a DDR1-SHP2 axis that suppressed STAT1 phosphorylation, silencing tumor-cell immune-engagement programs. NECTIN4 blockade restored STAT1 activity and reduced tumor growth, indicating that the cloaked state is pharmacologically reversible. Mutational signature, breakpoint motif, timing and clonality analyses, together with APOBEC3B expression and germline genetic evidence, linked APOBEC3-mediated mutagenesis to recurrent 1q23.3 amplification encompassing NECTIN4. These findings reveal how neoantigen-generating mutational processes can be coupled to structural genome evolution to enable tumor-intrinsic immune cloaking through a therapeutically targetable NECTIN4-DDR1-SHP2 axis.

cancer biology↗